Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing

Zhao, Qianying; Yang, Jiaxin; Li, Lei; Cao, Dongyan; Yu, Mei; Shen, Keng

doi:10.3802/jgo.2017.28.e39

Cited by 31 publications

(39 citation statements)

References 36 publications

(59 reference statements)

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“…The quality of the data that can be obtained from FFPE tissues as opposed to fresh tissues needs clarification. The fact that the distribution of somatic mutations was consistent with other Chinese studies (36,48) and with a Polish study using FFPE tissues from HGSC patients (52) could guarantee the quality of our sample preparation. It was suggested that an adjusted targeted capture-based enrichment protocol was superior to commonly applied multiplex PCRbased protocols for reliable BRCA1/2 variant detection, including CNV detection, using FFPE tumor samples (53).…”

Section: Discussionsupporting

confidence: 87%

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

You

et al. 2020

Front. Oncol.

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Objective: Despite several nationwide cohort studies of germline BRCA1/2 mutations and several small cohort studies of somatic BRCA1/2 mutations in Chinese epithelial ovarian cancer (EOC) patients, little is known about the impact of these findings on survival outcomes in this population. In this study of 172 retrospectively recruited Chinese EOC patients, germline and somatic BRCA1/2 mutations and their value for predicting survival outcomes were evaluated. Methods: Unselected patients who visited the study center from January 1, 2011, to January 1, 2015, were recruited and asked to provide peripheral blood samples for this study if they were pathologically confirmed to have primary EOC. All patients received staging surgeries or debulking surgeries involving systemic platinum-based chemotherapy, and the patients were then followed up to December 1, 2017. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections and peripheral blood and sequenced for somatic and germline testing, respectively. The demographic and clinicopathological characteristics of the patients were collected to analyze the distribution of BRCA mutations in subgroups. Survival outcomes were compared among various BRCA mutation statuses using univariate and multivariate models. Results: In 58 (33.7%) patients, 63 variants were identified, including variants of unknown significance (VUS) in 18 patients (10.5%) and pathogenic or likely pathogenic variants in a partially overlapping set of 41 patients (23.8%). Germline BRCA mutations, somatic BRCA mutations, BRCA1 mutations in general, and BRCA2 mutations in general were found in 35 (20.3%), 7 (4.1%), 28 (16.3%), and 13 (7.6%) patients, respectively. Five recurrent mutations were identified. Personal and family cancer histories as well as hereditary breast and ovarian cancer (HBOC) criteria were associated with deleterious BRCA mutations both overall and in the germline specifically, whereas only age at diagnosis of EOC was associated with somatic BRCA mutations. In univariate and Cox regression analyses, patients with BRCA1/2 mutations in general had significant improvements in progression-free survival (PFS) and overall survival (OS). You et al. Germline and Somatic BRCA1/2 Mutations in EOC Conclusions: In Chinese EOC patients, the distributions and risk factors associated with germline and somatic BRCA1/2 mutations were similar to those previously reported in international studies. Deleterious BRCA mutations in general were associated with improved survival outcomes in this cohort.

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Section: Discussionsupporting

confidence: 87%

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

You

et al. 2020

Front. Oncol.

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“…Previous studies have presented the involvement of radiation repair protein 52 (RAD52) in the cell cycle control as well as DNA repair, and depletion of RAD52 could cause synthetic lethality in BRCA1 mutant breast cancer cells (Hromas et al, 2017). Additionally, several groups have conferred RAD52 as novel risk loci in ovarian cancer patients (Stafford et al, 2017; Zhao et al, 2017), underlining its significant effects on controlling cancer cell activities. In conclusion, all elements in these five triplets contribute cohesively to the development of ovarian cancer through regulating cell cycle and growth.…”

Section: Resultsmentioning

confidence: 99%

The Identification and Analysis of mRNA–lncRNA–miRNA Cliques From the Integrative Network of Ovarian Cancer

Zhou

Zheng

et al. 2019

Front. Genet.

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Ovarian cancer is one of the leading causes of cancer mortality in women. Since little clinical symptoms were shown in the early period of ovarian cancer, most patients were found in phases III–IV or with abdominal metastasis when diagnosed. The lack of effective early diagnosis biomarkers makes ovarian cancer difficult to screen. However, in essence, the fundamental problem is we know very little about the regulatory mechanisms during tumorigenesis of ovarian cancer. There are emerging regulatory factors, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), which have played important roles in cancers. Therefore, we analyzed the RNA-seq profiles of 407 ovarian cancer patients. An integrative network of 20,424 coding RNAs (mRNAs), 10,412 lncRNAs, and 742 miRNAs were construed with variance inflation factor (VIF) regression method. The mRNA–lncRNA–miRNA cliques were identified from the network and analyzed. Such promising cliques showed significant correlations with survival and stage of ovarian cancer and characterized the complex sponge regulatory mechanism, suggesting their contributions to tumorigenicity. Our results provided novel insights of the regulatory mechanisms among mRNAs, lncRNAs, and miRNAs and highlighted several promising regulators for ovarian cancer detection and treatment.

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“…Estimates of the contribution of germline BRCA mutations to EOC vary widely, from 5% to 20% [20], and patients having somatic mutations without germline mutations in BRCA are less frequent, accounting for 2%-8% [21][22][23][24]. Germline and somatic BRCA mutation frequencies in EOC patients, according to the published literature, are listed in Table 5 [4, [23][24][25][26][27]. As for HGSC, the lowest frequency of germline and somatic BRCA mutations (21.8%) is recorded in TCGA 2011 data, with the highest (20/47, 42.6%) in the present study.…”

Section: Discussionmentioning

confidence: 99%

Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma

et al. 2020

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PurposeIn this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.Materials and MethodsTissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison.ResultsBRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53mutation, exhibited better disease-free survival than those with TP53 mutation alone.ConclusionDNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

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Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing

Cited by 31 publications

References 36 publications

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

The Identification and Analysis of mRNA–lncRNA–miRNA Cliques From the Integrative Network of Ovarian Cancer

Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma

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